Abstract: The primary objective of this K01 application is to provide research training and mentorship to the candidate to enable her to become an independent medical rehabilitation researcher. The candidate has clinical experience in Physical Therapy and doctoral training in basic neurobiology and is transitioning to a new clinical research area investigating balance and gait in a neurodegenerative disorder called Fragile X Tremor and Ataxia Syndrome (FXTAS) which occurs in some premutation (PM) carriers of the Fragile X (FMR1) gene. The short term goals are to develop an early detection model for FXTAS and identify additional molecular risk factors for developing this disorder. The plan has 3 aims: 1) To identify quantitative markers of balance and gait impairments in PM carriers with and without FXTAS, 2) To determine the impact of executive function and cognitive interference on balance and gait function in PM carriers with and without FXTAS, and 3) to determine the relationship between age, sex, executive function, and FMR1 molecular variables and the presence and severity of balance and gait impairment in PM carriers with and without FXTAS. The candidate?s long term scientific goal is to become a leading independent research scientist in movement neuroscience and neurological disorders and in the precise identification of balance and gait dysfunction in FXTAS from the earliest stage. In order to reach these goals the candidate needs to develop expertise in patient outcomes and neuroepidemiology research. The candidate?s short term goals which form the basis for this five year K development plan include training in 1) large scale subject recruitment, data management and advanced biostatistics, 2) balance and gait analysis and application to clinical trials in movement disorders, 3) design, implementation and analysis of large scale epidemiological studies and 4) introduction to rehabilitation intervention and clinical trial research methodology. Results of this research will help clarify neurological mechanisms underlying balance and gait deficits in FXTAS, establish reliable and quantitative outcomes measures of motor impairment, and provide data for future clinical rehabilitation trials. This research will be the first step in characterizing the longitudinal history of motor dysfunction in FXTAS from its earliest stages, thus paving the way for establishing disease monitoring and modifying strategies in premutation carriers. This proposal is relevant to the NIH Research Plan on FXS and Associated Disorders which includes the following goals: 2.2 validation of quantitative instruments to detect early clinical signs of FXTAS and its progression, 2.3 identification of molecular and clinical risk factors in individuals associated with penetrance of FXTAS, and 2.5 defining genotype, including FMR1 molecular factors, and clinical phenotype relationships in FXTAS.